There is growing evidence for a modulatory role of serotonergic (5-HT) mechanisms in the abuse-related effects of cocaine in animals and humans. Our previous research showed that pharmacological inhibition of 5-HT uptake results in a dose-dependent attenuation of the discriminative stimulus (DS) effects of cocaine in monkeys, consistent with recent findings that 5-HT uptake inhibitors (e.g. Prozac ) can attenuate the subjective effects of cocaine in people. Less is known, however, about the role of different 5-HT receptor subtypes in mediating the cocaine-modulating effects of 5-HT. To address this issue, we have investigated the effects of receptor subtype-selective 5-HT agonists and antagonists in monkeys trained to discriminate cocaine from vehicle using procedures similar to those of our initial experiments. Among the drugs evaluated were the 5-HT1A agonists 8-OH-DPAT and buspirone, the 5-HT1B/2C agonist mCPP, the 5-HT2C agonist TFMPP, the nonselective 5-HT agonist quipazine, the 5-HT1A antagonist NAN 190, and the 5-HT2A/2C antagonist ritanserin. Each compound was studied first for its capacity to reproduce the DS effects of cocaine and, as warranted, to modify cocaine's DS effects when administered as a pretreatment. Of the compounds tested, only quipazine engendered consistent increases in cocaine-appropriate responding. Although full substitution for cocaine was typically not observed, quipazine engendered at least partial substitution in all monkeys. Additionally, the cocaine-like effects of quipazine (but not the effects of cocaine itself) were antagonized by ritanserin, and quipazine enhanced the DS effects of cocaine in an additive fashion. Pretreatment with other 5-HT receptor agonists or antagonists, however, did not produce consistent changes in the cocaine dose-response function regardless of dose. Although our findings support the prevailing view that 5-HT mechanisms play a modulatory role in the behavioral effects of cocaine, the relatively modest effects seen with most of the 5-HT compounds provide only limited encouragement for the development of these drugs as pharmacotherapies for cocaine abuse.